Procaine penicillin



March 20, 1956 B, N ETAL 2,738,093

PROCAINE PENICILLIN Filed March 51. 1950 IN VEN TORS N B. cow/w BY SARA1.. NORMAN MZW Q,

ATTORIVE 2,739,098 PROCAINE PENICILLIN John B. Conn, Westfield, and SaraL. Norman, New

Brunswick, N. 3., assignors to Merck & Co., Inc., Rahway, N. J acorporation of New Jersey Application March 31, 1950, Serial No. 153,2446 Claims. (Cl. 161-65 This invention relates generally to new.therapeutic preparations and, moreparticularly, to a new crystal form ofprocaine-benzylpenicillin adapted for use in parenteral suspensions, andto methods by, which this new crystal form may be prepared.

Procaine-benzylpenicillin, a compound formed by reacting procaine withbenzylpenicillin in equimolecular proportions, is valuable inthetr'eatment of various diseases. Since procaine-benzylpenicillin issparingly soluble in water and in other liquids suitable for parenteraladministration, it has been proposed to adminster this compound in theform of suspensions. 1

However, procaine-benzylpenicillin normally crystallizes in the form ofneedles and it has been observed that the administration of suspensionsof needle-shaped crystals of procaine-benzylpenicillin is hazardous andcauses serious diificulty. V

In a syringe filled with a suspension of needle-shaped crystals ofprocaine-benzylpenicillin, obstruction is usually observed when pressureis applied to the syringe piston. Thus, the administration of such asuspension is always troublesome and adds materially to the discomfortof the patient.

We have now discovered that it is possible to prepare a new crystal formof procaine-benzylpeniciliin and in this form procaine-benzylpenicillinis particularly suitable for the parenteral administration ofsuspensions of this compound. i i i The new crystals ofprocaine-benzylpenicillin prepared in accordance with our inventionpossess a polyhedral or platelet form which is particularly adapted forpassage through a syringe needle. Thus, a suspension of crystal,- lineprocaine-benzylpenicillin having the shape of a platelet passes withoutdifficulty through the narrow opening of the syringe needle.

We have found that the crystal growth habit of procaine-benzylpenicillinis completely altered whenthe reaction of procaine with benzylpenicillinis carried out in the presence of a Water soluble cellulose ether suchas methyl cellulose.

While a very small amount of methylcellulose is required for thepreparation of the new crystal form of procaine-benzylpehicillin, it isalways advantageous to employ methyl cellulose in aconcentration'greater'than 0.05%.

When lower concentrations of methyl cellulose are employed such as, forexample, 0.02% or less, a mixture of crystals is obtained containingboth the needle form. and the blunt polyhedral form. When concentrationshigher than 0.05% are utilized, the resulting procaine-benzylpenicillinis always recovered in platelet form which is particularly desirable foruse in parenteral suspensions. The intermediate blunt polyhedral form,usually obtained when methyl cellulose is employed in aconcentration ofabout 0.05% or less, is less satisfactory for use in parenteralsuspensions than the platelet form.

The new platelet form of crystals of procaine benzylw shaped crystals.The length of the platelets is of th same order as their width, whereasthe length of the needle is approximately 3 to 6 times as greatasthewidth.

.A comparison of the old and new crystal forms ofprocaine-benzylpenicillin is illustrated in the accompanying drawing inwhich Figure 1 represents the needle form and Figure 2 shows the newplatelet form.

Inpreparing the new crystal form of procaine-benzylpenicillin in apreferred manner, a salt of benzylpenicillin is reacted with a salt ofprocaine. The salts of procaine which are particularly suitable for thisreaction are the water soluble salts such as, for example, procainehydrochloride. Among the salts of benzylpenicillin which may be used forthis reaction are, for example, sodium benzylpenicillin,N-ethyl-piperidine-benzylpenicillin and other It is usually preferableto employ equipurified by washing in accordance with conventionalprocedures.

The following examples illustrate methods of carrying out the pesentinvention, but it is to be understood that these examples are given byway of illustration and not of limitation.

EXAMPLE 1 p To a solution of 27.3 g. (0.1Jmole) of procainehydrochloride in 500 ml. of 1%aqueous methyl cellulose wasadded asolution of 35.6 g. (0.1 mole) sodium-benzylpenicillinate in 500 ml. 1%aqueous methyl cellulose with continuous stirring at room temperature.After an induction period of a few minutes procaine benzylpenicillinatecrystallized in the form of minute flat platelets which were recoveredby filtration, washing and drying.

The crystals were mixed with buffered penicillin G In 29 trials sodiumand tested for injectability in rabbits. there was no bloclcingobserved.

In a comparable control experiment using a formu'lation containing theneedle form there was blocking in .16

out of 62 trials.

EXAMPLE 2 To a solution of 22.5 g. (0.05 mole) N-ethyl piperidinebenzylpenicillinate in 250 m1. of 0.1% aqueous methyl cellulose wasadded with stirring a solutionof 13.8 g.

(0.05 mole) procaine hydrochloride in 250 ml. of 0.l%

aqueous methyl cellulose. The platelet form of procainepenicillin,recovered as in Example I, weighed 22.0 g.

EXAMPLE 3 EXAMPLE 4 Proceeding as in Example 3, but using methylcellulose at 0.01 to 0.02% concentration, theprocaine-benzylpenicillinate crystals were found to consist of a mixtureof blunt polyhedral forms and needles.

A solution of a procaine salt in aqueous 3 EXAMPLE 5 A formulation wasprepareclusing 2 g. procaine-penicillin G platelets, 425 mg. penicillinG potassium salt, 133 mg. anhydrous sodium citrate, and 32 mg; anhydroussodium-carboxy methyl cellulose. This was. prepared for a 5 dose vial,to which was added-4.5" cc. water andith'cwhole shaken, resulting 6.4cc. of an aqueous-1 suspension.

The suspension contained 300,000 unitsofprocainepenbblocking when usedin animals.

The. different crystal forms-Were COIRPEIIBKTBY physical" measurements.Dimensional measurementsof twoa-verage;preparations of the needle. formand the new platelet form areas follows:

Needles 1 FDA- Percent, Range (IL) of Total x55? Number Percent 3. 9252. 2 14. 4 5. 62 34: 2 31; 3 7. 09 10. 2 21. 2 13. 5 2-1 12. s 15. U0.4 3. 7 20. 0. 9. 1G. 6

'FDA Percent a as ant m an Percent;

-14 5-l4 66. O 6. -29 15-29 1319- 7. 30-49 3049 10. 1. 17. -6 a 50-69'5. 3 21. 70-99 70-99 3. 8 30. 100-149 100-149 0. 9 15.

1 FDA: Federal Drug Administration procedure ,describedin Tests andMethods of Assay nnd'Certification of-Antibiotics vol. I, section 141.7(D) Measures of Penicillin. Particles:

We claim:

1': The process" of preparingprocaine-benzylpenicillin crystals inplatlet form, which comprises reacting a water soluble benzylpenicillinsalt with a Water soluble salt of procaine in an aqueous solutioncontaining a small amount of methyl cellulose.

2. The process of preparing procaine-benzylpenicillin crystals inplatlet-form, whichcomprises reacting a water soluble benzylpenicillinsalt with a water soluble salt of procaine'iman aqueousz'solutioncontaining at least 0.05% methyl cellulose.

3. Crystalline procaine=benzylpenicillin in the form ofplateletsihavingailength to:width: ratio of about 1.

4. The process for preparing procaine penicillin crystals in modifiedform which" comprises reacting procaine hydrochloride with a Watersoluble salt of penicillin in an aqueous solution containing a smallamount of methyl cellulose.

5. Inthe. process of preparing. procainerbenzylpenicillin crystals.inpla-tlet form, the. step whichcomprises crystallizingprocaine-benzylpenicillin.from an aqueous solution containing a smallamount of methylcellulose.

6. A pharmaceutical composition suitable for. parenteral. administrationcomprising an aqueous suspension. of crystallineprocaine. benzylpenicillin in the form of plateletshaving a-lengthto width ratio ofvabout one.

RefcreucesCitedin the file of this patent- UNITED STATES PATENTS2,177,269 Sullivan Oct. 24, 1940 2,236,545- Maxwell Apr; 1, 19412,445,478 Foster et a1. JulyZO, 1948 2,446,974 Chow- Aug. 10, 19482,515,898 Rhodehamel July 18, I950 OTHER. REFERENCES

6. A PHARMACEUTICAL COMPOSITION SUITABLE FOR PARENTERAL ADMINISTRATION COMPRISING AN AQUEOUS SUSPENSION OF CRYSTALLINE PROCANINE BENZYL PENICILLIN IN THE FORM OF PLATELETS HAVING A LENGTH TO WIDTH RATIO OF ABOUT ONE. 